The BioCycle Study was a prospective cohort study of menstrual cycle function among 259 regularly menstruating, healthy, premenopausal volunteers aged 1844 years from western New York State conducted from 2005-2007. Women were not using hormonal contraception and were followed for one (n=9) or two (n=250) menstrual cycles with fasting morning blood samples collected in each cycle during early menstruation, mid- and late-follicular phase, two days around expected ovulation, and early, mid-, and late luteal phase. The study was very successful with 94% of women completing at least 7 of 8 clinic visits per cycle. The primary findings of this observational study were published in 2010 and described an independent positive association between F2-isoprostane levels and estradiol, a result which called into question the commonly held hypothesis that endogenous estradiol reduces oxidative stress. In addition to epidemiologic methods development work, recent secondary work from this study crosses four domains of reproductive health and menstrual cycle function: variability in endocrine biomarkers across cycle, environmental impacts on reproduction, reproductive dysfunction and subclinical pathology, and lifestyle impacts on associations with reproductive function. Variability across the cycle: A key feature of the BioCycle study has been the ability to examine variation in biomarkers across the menstrual cycle, an important consideration that impacts measurement error in studies including premenopausal women and also impacts the development of clinical cut-points and clinical decision making when specimen timing does not account for cycle phase. This collective body of work reveals the variation in biomarkers commonly used in research and clinical settings that occurs uniquely in premenopausal women, corresponding to continual, cyclic changes in reproductive steroid hormones and gonadotropins. These data aid researchers utilizing biomarker measures in studies of premenopausal women to reduce measurement error and highlight the importance of considering menstrual cycle phase as an important source of biological variability when interpreting clinical findings. Environmental impacts on menstrual cycle function: Other work examined blood contaminant metals in this population of healthy premenopausal women with environmentally relevant levels of exposure (as opposed to occupational or disaster exposures) and demonstrated that blood cadmium, lead, and mercury were not associated with elevated lipid peroxidation biomarkers nor reduced bone mineral density, but that blood lead was associated with decreased glomerular filtration rate and increased creatinine. Evidence of genotypic differences which may explain susceptibility to the negative effects of certain environmental contaminants on cardiovascular health was also discovered. Menstrual cycle dysfunction: Another unique feature of the BioCycle study was the capture of detailed prospective information on factors related to known clinical pathologies or other reproductive dysfunction. Building on prior characterization of sporadic anovulation in this cohort, the team reported that estradiol, progesterone, and LH pea) concentrations were lower during the ovulatory cycle of women also having an anovulatory cycle during study participation, compared with women having two ovulatory cycles. Such findings indicated sporadic anovulation may actually indicate a chronic, underlying insufficiency in ovulatory function. Along these lines, more frequent anovulation was also reported among women having higher testosterone and greater AMH, a marker of antral follicle count, providing evidence that the endocrine characteristics of polycystic ovary syndrome, a highly prevalent cause of menstrual cycle disturbance and infertility, may occur along a continuum even in healthy women. Additionally, luteal phase deficiency (LPD), a poorly characterized pathology among women, was characterized using two classification schemes. Estradiol was lower in LPD cycles under either criterion, but LH and FSH were lower only in association with shortened luteal phase (i.e., clinical LPD), indicating that clinical and biochemical LPD (based on progesterone concentration) are both prevalent, but may reflect different underlying mechanisms. Lifestyle and behavior impacts on menstrual cycle function: With daily questionnaires including womens perceived stress, activities, and health behaviors, the BioCycle study also produced numerous reports describing the impact of time-varying lifestyle and behavior practices on menstrual cycle function and reproductive hormones. For example, a report demonstrated that high daily stress was associated with lower estradiol, lower LH, higher FSH, lower luteal progesterone, as well as sporadic anovulation, all indicators of compromised ovulatory function. Also, a provocative finding was that sexual activity was linked to hormones and ovulatory function, as elevated concentrations of estrogen, luteal progesterone and mid-cycle LH, coupled with lower odds of sporadic anovulation, were observed in sexually active women compared with sexually inactive (i.e., virgin) women, even after controlling for potentially confounding factors such as age. Typical medication use was characterized and another report demonstrated that over-the-counter (OTC) pain medication use, reported by 68% of women, was associated with decreased odds of sporadic anovulation. Collectively, the total body of BioCycle findings, combined with the studys methodological work, has been pioneering in understanding many important and novel questions related to normal menstrual cycle and ovulatory function, as well as a continuum of reproductive dysfunction.
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